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Table 1 Male individuals with CASK mutations

From: Phenotypic and molecular insights into CASK-related disorders in males

Patient

CASK mutation

Birth OFC/W/L (SD)

Age

OFC a (SD)

Height a (SD)

Weight a (SD)

DD/ID

Tonus

Seizures EEG

Other neurologic anomalies

Eye findings

Sensorineural hearing loss

Other anomalies

Face

MRI

Overall phenotype

Pat 1

c.704_708del p.K236Efs*10 ex 7 dn

w 37 +3 -4.2/-3.2/?

† at 7 m

−5.9 (4.5 m)

−4.8 (6 m)

−1 (6 m)

profound, no development

severe hypotonia

intractable seizures

apnoeas, inability to swallow

optic atrophy

+

ASD, bil. clubfeet

dolichocephaly, puffy eyelids, broad nasal bridge, bulbous tip of nose, severe retromicrognathia, ear dysplasia, fleshy ear lobes

severe hypo CBL + pons + medulla, simplified gyri, cortical atrophy

MICPCH Severe epilepsy

Pat 2

Dup ex 10–16 dn

w 37 +3 -2.5/-1.9/-1.5

10 m † at 21 m

progressive microcephaly

−2.4

−2.8

profound

severe hypotonia

probably Ohtahara s., burst suppression

 

macropapilla, optic atrophy?

+?

long convex fingernails, overriding 2nd toes, linear blisters right leg, needed PEG

retrognathia, fleshy uplifted ear lobules

significant hypo CBL + pons

MICPCH Severe epilepsy

Pat 3

c.1A > G ex 1 dn

−1.3/-0.3/?

5 y

−5 (3 y)

−3

−2

profound, no development

severe hypotonia

intractable seizures

 

opticus hypoplasia

AVSD, tapering fingers, edema of the dorsum of hands and feet, needed PEG

long eyelashes, short nose, large ears with fleshy uplifted ear lobules

small brain, hypo CBL + pons

MICPCH Severe epilepsy

−3.7 (5 y)

Pat 4

c.79C > T p.R27* ex 2 dn

w 33 +2 -2.57/-1.14/-1.73

15 m

−9.0

−3.0

−1.67

profound

severe hypotonia

intractable seizures, burst suppression

apnoea-bradycardy-syndrome, inability to swallow

optic atrophy?

 

VSD, short limbs, contractures of fingers

plagiocephaly, metopic ridge

severe hypo CBL + pons, progressive cortical atrophy, progressive hypomyelination

MICPCH Severe epilepsy

Pat 5

Dup ex 4–20 mos

w 36 +1 -1.8/0/0.3

7 m

−7.8 (9 m)

−2.1 (9 m)

−0.6 (9 m)

severe

hypertonia

spasms and myoclonic seizures, no hypsarrhythmia

hyperopia

?

micropenis, cryptorchidism

sparse hair, broad nasal bridge, epicanthal folds, long philtrum, retromicrognathia, fleshy uplifted ear lobules

small brain, hypo CBL + pons

MICPCH epilepsy

Pat 6

Del ex 1 mos

−2.9/-1.1/-1.7

16 m

−6 (11 m)

−2 (11 m)

−1.6 (11 m)

severe

hypertonia of limbs

hyperopia, strabism

cryptorchidism

broad nasal bridge, epicanthal folds, long philtrum, prominent premaxilla, mild retrognathia, simple/thin auricle

hypo CBL + pons

MICPCH

Pat 7

Del ex 3–9 mos

w 37–0.93/-0.5/-0.87

29 m

−3.56 (29 m) -2.55 (5;3 y)

−3.5 (29 m) -2.42 (5;3 y)

−1.97 (29 m) -1.45 (5;3 y)

severe

tonus regulation disorder

mild ataxia

prominent nasal bridge, thin upper lip, pointing chin

mild hypo CBL + pons mildly simplified gyri

MICPCH

Pat 8

Dup ex 1–5 mat

−2 /0/-1.4

20 m

−5

−2

−2

Mild to moderate DD

 

  

FTT

long flat philtrum

mildly smaller frontal lobes, small CC (frontal), CBL and otherwise normal

MIC + DD

Pat 16b

c.1061T > C p.L354Pc ex 12

 

5 y

   

profound, no development

 

West s., intractable seizures

    

large eyes, large ears, broad nasal bridge, broad nasal tip, epicanthal foldsd

MICPCH

MICPCH Severe epilepsy

Pat 1e

Del ex 2 matf

−1.2/-2/-1.4

4 y

−2.7 (1.4 y)

  

profound

 

Ohtahara s.

   

Long slender fingers, micropenis, needed tracheostomy + PEG

micrognathia, short neck

severe hypo CBL, hypo ponsd

MICPCH Severe epilepsy

Pat 2e

c.1A > G ex 1 dn

−2.7/-3.3/-2.8

4 y

   

severe

hypertonia of limbs

Ohtahara s.

 

PHPV

short upper arms, overlapping fingers, clinodactyly

micrognathia, high arched palate

severe CBL hypo, hypo ponsd

MICPCH Severe epilepsy

Case reportg

c.227_228del p.E76Vfs*6 ex 3 dn

0/0.1/1.4

8 m

−5.4

  

severe

hypotonia

early myoclonic encephalopathy (EME)

dystonia, chorea

optic atrophy

 

CP, tetralogy of Fallot, AMC, hydronephrosis, VUR, needed tracheostomy

micrognathia

severe hypo CBL + pons

MICPCH Severe epilepsy

Pat 13h

c.278 + 1G > A in 3 dn

−2/0/-0.5

16 m

−6

−2

 

profound

profound hypotonia

intractable seizures, spasms + tonic seizures, suppression-burst

spastic tetraparesis, dystonia

optic atrophy

 

long slender fingers with contractures, needed PEG

retrognathia, high arched palate, low-set ears with prominent lobules, down-slanted palpebral fissures, broad nasal bridge

very severe hypo CBL, hypo pons

MICPCH Severe epilepsy

Pat 12h

c.316C > T p.R106* ex 4 mos

−3/-1.5/-2

15 y

−3.5

−3.5

 

severe

 

dystonia, dyskinesia

 

well-arched eyebrows, broad nasal bridge, hypertelorism?, anteverted nares, full lipsd

mild hypo CBL

MICPCH

Pat 5i

c.915G > A p.(=) ex 9 dn

 

† at 2 w

microcephaly

    

?

     

severe hypo CBL + pons, thin and unmyelinated CC

MICPCH

Pat II 4j

Fam V c.2183A > G p.Y728C ex 23 (2 ♂)

 

14 y

−4.4k

−2.9

thin

severe

   

N, strabism, optic atrophy

  

synophris, high nasal bridge, upslanted palpebral fissures, short columellad

hypo CBL, pachygyria

MICPCH + N

Pat II 2j

 

19 y

−2.4k

−1.7

thin

moderate

   

N, astigmatism

  

similar to II 4

ND

MIC + Moderate ID + N

Pat IV 1j,l

Fam 74 c.2129A > G p.D710G ex 22 (4 ♂)

 

42 y

normal

normal

 

mild

  

hand tremor

N, strabism

  

no dysmorphism

ND

Mild ID + N

Pat III 3j,l

  

98th cen

normal

obese

mild

  

tremor, unsteady gait

N, strabism

   

ND

Mild ID + N

Pat III 12j,l

  

98th cen

normal

obese

mild

   

N

   

normal

Mild ID + N

Pat III 6j,l

 

59 y

normal

normal

 

mild

      

no dysmorphism

ND

Mild ID

Pat IV 1j,l

Fam 16 c.802T > C p.Y268H ex 8 (4 ♂, 1 without clinical description)

  

normal

normal

 

severe/profound

 

+

toe walker

no N

 

autistic

no dysmorphism

ND

Severe ID

Pat III 4j,l

     

severe

 

+

 

no N

   

ND

Severe ID

Pat II 3j,l

     

severe

  

toe walker

no N

 

obsessive behaviour

 

ND

Severe ID

three Patj,l

Fam 123 c.2756T > C p.W919R ex 27 (3 ♂)

  

normal

tall

 

mild

 

+, in one of three patients at age 17 y

 

N

  

no dysmorphism

ND

All 3: Mild ID + N

Pat III 1j,l

Fam 245 (K8919) c.1186C > T p.P396S ex 13 (4 ♂, 2 without clinical description)

 

58 y

0

short stature, 152 cm

 

profound

  

tremor, unsteady gait

   

flat mid face, open mouth, eversion of lower lip

ND

Severe IDS

Pat III 4j,l

 

52 y

0

short stature, 147 cm

 

severe

   

strabism

  

flat nasal bridge, anteverted nares, wide mouth, broad palate, broad grooved tongue, short broad neck

ND

Severe IDS

Pat III 3j

Fam 683 c.2521-2 A > T in 25 (4 ♂)

 

46 y

+1.6

−2.2

 

mild

 

+, absences

N, high myopia

  

no dysmorphism

ND

Mild ID + N

Pat II 3j

     

mild

 

+

 

N, strabism, myopia, astigmatism

   

ND

Mild ID + N

Pat II 4j

     

mild

 

 

N, high myopia, optic atrophy, retinal pigment anomalies

   

ND

Mild ID + N

Pat II 5j

     

mild

 

+

 

N

   

ND

Mild ID + N

Pat III 26m

c.83G > T p.R28L ex 2 (3 ♂)

 

2 y

relative macrocephaly

50-75th cen

25-50th cen

marked

hypotonia

EEG mildly abnormal

 

+

hyperactivity, aggressive behaviour, constipation

prominent forehead, frontal upsweep, hypertelorism, depressed nasal bridge, long philtrum, micrognathiad

normal (on CT)

IDS

Pat II 11m

 

34 y

relative macrocephaly

  

profound

hypotonia in infancy

+

   

aggressive behaviour, constipation

prominent forehead, hypertelorism, broad long philtrumd

ND

IDS

Pat II 17m

 

16 y

 

short stature

 

+, unspecified

hypotonia in infancy

   

+

hyperactivity, constipation, cryptorchidism

prominent forehead, frontal upsweep, long philtrum, epicanthal foldsd

ND

IDS

  1. Legends: The eight first listed patients (Pat 1-8 in bold) are described in detail in the manuscript, patients listed below have been reported previously. +, present; −, absent; †, died; AMC, arthrogryposis multiplex congenita; ASD, atrial septal defect; AVSD, atrioventricular septal defect; bil., bilateral; CBL, cerebellum; CC, corpus callosum; cen, centile; CP, cleft palate; CT, computed tomography; DD, developmental delay; Del, deletion; dn, de novo; Dup, duplication; EEG, electroencephalogram; ex: exon; F, female; Fam, family; FTT, failure to thrive; hypo, hypoplasia; ID, intellectual disability; IDS, syndromic intellectual disability; in, intron; L, length; m, months; mat, maternally inherited; MIC, microcephaly; MICPCH, microcephaly with pontine and cerebellar hypoplasia; mos, somatic mosaicism; MRI, magnetic resonance imaging; N: nystagmus; ND, not documented; OD, right eye; OS, left eye; Pat, patient; PEG, percutane g-tube; PHPV, persistent hyperplastic primary vitreous; s., syndrome; SD, standard deviation; VSD, ventricular septal defect; VUR, vesicoureteral reflux; W, weight; w, week of gestation; y, year(s).
  2. aat last follow up (if not specified otherwise).
  3. bTakanashi et al., 2012 [5].
  4. cin original publication wrongly reported as p.L348P.
  5. dbased on figures/photographs shown in publication.
  6. eSaitsu et al., 2012 [9].
  7. fthe mother is a somatic mosaic for the CASK mutation.
  8. gJinnou et al., 2012 [18] and Nakamura et al., 2014 [8].
  9. hBurglen et al., 2012 [2].
  10. iNajm et al., 2008 [1].
  11. jHackett et al., 2010 [10].
  12. kin Table 1 of the original publication wrongly listed as normocephaly (absolute values were given in the text).
  13. lTarpey et al., 2009 [12].
  14. mPiluso et al., 2003 [19] and 2009 [11].